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Roles of Adenosine Receptor (subtypes A1 and A2A) in Cuprizone-Induced Hippocampal Demyelination

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Abstract

Hippocampal demyelination in multiple sclerosis (MS) has been linked with cognitive deficits, however, patients could benefit from treatment that induces oligodendroglial cell function and promotes remyelination. We investigated the role of A1 and A2A adenosine receptors (AR) in regulating oligodendrocyte precursor cells (OPCs) and myelinating oligodendrocyte (OL) in the demyelinated hippocampus using the cuprizone model of MS. Spatial learning and memory were assessed in wild type C57BL/6 mice (WT) or C57BL/6 mice with global deletion of A1 (A1AR-/-) or A2A AR (A2AAR-/-) fed standard or cuprizone diet (CD) for four weeks. Histology, immunofluorescence, Western blot and TUNEL assays were performed to evaluate the extent of demyelination and apoptosis in the hippocampus. Deletion of A1 and A2A AR alters spatial learning and memory. In A1AR-/- mice, cuprizone feeding led to severe hippocampal demyelination, A2AAR-/- mice had a significant increase in myelin whereas WT mice had intermediate demyelination. The A1AR-/- CD-fed mice displayed significant astrocytosis and decreased expression of NeuN and MBP, whereas these proteins were increased in the A2AAR-/- CD mice. Furthermore, Olig2 was upregulated in A1AR-/- CD-fed mice compared to WT mice fed the standard diet. TUNEL staining of brain sections revealed a fivefold increase in the hippocampus of A1AR-/- CD-fed mice. Also, WT mice fed CD showed a significant decrease expression of A1 AR. A1 and A2A AR are involved in OPC/OL functions with opposing roles in myelin regulation in the hippocampus. Thus, the neuropathological findings seen in MS may be connected to the depletion of A1 AR.

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Data Availability

The supporting data of this study are available from the corresponding author upon reasonable request.

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Funding

This study received support (for subsistence only) from the US Department of States, Bureau of Educational and Cultural Affairs via the Fulbright Foreign Program awarded to OEA for a Research Visit to Cornell University.

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  1. Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA

    Olamide E. Adebiyi & Margaret S. Bynoe

  2. Department of Veterinary Physiology and Biochemistry, Faculty of Veterinary Medicine, University of Ibadan, Ibadan, Nigeria

    Olamide E. Adebiyi

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OEA carried out the experiment, analyzed the data, drafted the manuscript, and designed the figures. MSB conceived the original idea and supervised the experiments. All authors discussed the results and contributed to the final manuscript.

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Correspondence to Olamide E. Adebiyi or Margaret S. Bynoe.

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All the mice were housed in a sterile facility and maintained following National Institute of Health guidelines for care and use of laboratory animals. The study was approved by the Institutional Animal Care and Use Committee of our university (Protocol # 2008–0092).

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Adebiyi, O.E., Bynoe, M.S. Roles of Adenosine Receptor (subtypes A1 and A2A) in Cuprizone-Induced Hippocampal Demyelination. Mol Neurobiol 60, 5878–5890 (2023). https://doi.org/10.1007/s12035-023-03440-6

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